Various compounds have been investigated as PDE-4 inhibitors, on which the present invention is based, in order to develop therapeutic agent for asthma and chronic obstructive pulmonary diseases [Peter Norman, Expert Opin. Ther. Patents. 2002, 12(1), pp 93-111]. Among them, the most representative compounds are Rolipram [EP 0660711, Jul. 5, 1995], Cilomilast [U.S. Pat. No. 6,013,827, Jan. 11, 2000] and Roflumilast [U.S. Pat. No. 5,712,298, Jan. 27, 1998].
Development of Rolipram, which had been firstly advanced into clinical studies, was ceased owing to its insignificant clinical effect and side effects such as vomiting.
Development of Cilomilast as a therapeutic agent for asthma was also ceased owing to its insufficient therapeutic effect on asthma, resulted of clinical studies. Clinical studies on chronic obstructive pulmonary disease (COPD) of the same compound are in progress [Peter Norman, Expert Opin. Ther. Patents 2002, 12(1), 93-111; Compton C, Edelson J D., Cedar E., Am. J. Respir. Crit. Care Med. 2001, 163, A909].
Roflumilast developed by Altana (Germany) has been known as the most effective compound [Zheng Huang, Yves Ducharme, Dwight Macdonald and Annette Robichaud, Current Opinion in Chemical Biology 2001, 5, 432-438], which showed excellent effect of inhibiting PDE-4 (IC50=0.8 nM), and noticeable effect on asthma and COPD in animal test [Armin Hatzelman and Christian Schudt, The Journal of Pharmacology and Experimental Therapeutics 2000, 297(1), 267-279; Daniela S. Bundschuh, Manfrid Eltze, Johannes Barsig, Lutz Wollin, Armin Hatzelmann, and Rolf Beume, The Journal of Pharmacology and Experimental Therapeutics 2001, 297(1), 280-290]. However, the approval as a therapeutic agent for asthma in Europe was withdrawn in 2005.
It has been also known that PDE-4 inhibitors also show effect of treating arthritis (USP 2003/0092706 A1), therapeutic effect on atopic dermatitis, leukemia, various cancers (Miles D. Houslay, Peter Schafer and Kam Y. J. Zhang, Drug Discovery Today, 2005, 10(22), 1503-1519) and effect of treating depression (U.S. Pat. No. 4,178,449, Dec. 11, 1979), and therapeutic effect on degenerative brain diseases such as Alzheimer's disease (Sophie L. Rovner, C&EN, 38, Feb. 21, 2005), as well as therapeutic effect on inflammatory pulmonary diseases such as asthma and chromic obstructive pulmonary disease.
Synthesis of 7-aryl-[1,2,4]-triazolo[1,5-a]pyrimidine derivatives, having similar structure to that of compound of Chemical Formula (1) according to the present invention has been reported (U.S. Pat. No. 5,127,936 (1992); U.S. Pat. No. 4,209,621 (1980)). But the compounds are not connected to preventing or treating asthma and chronic obstructive pulmonary disease, arthritis, atopic dermatitis, various cancers including leukemia and degenerative brain diseases.
Further, WO 06/071752 discloses triazolopyrimidine compounds represented by Chemical Formula (A), wherein methylamino or ethylamino group has been incorporated to 6-position of triazolopyrimidine. But the compounds simply include the compounds wherein dichlorophenyl is incorporated to Y, or the like. The disclosure relates to studies on therapeutic agent for diabetes, not to preventing or treating asthma and chronic obstructive pulmonary disease, arthritis, atopic dermatitis, various cancers including leukemia and degenerative brain diseases.

In addition, WO 02/02563 discloses triazolopyrimidine compounds (such as compounds represented by Chemical Formula B) having the similar structure to that of the compounds according to the present invention. However, the disclosure relates to only the studies on the compounds wherein mostly is a heterocyclic group (including very few cases wherein R1 is phenyl), without substantial studies on the compounds wherein R1 is a 3,4-dialkoxyphenyl. The studies simply relate to the compounds wherein at least one of R2 and R3 is (are) substituted by a substituent other than hydrogen, without studies on the compounds wherein both R2 and R3 are hydrogen. Moreover, with respect to the effect, the patent application describes only anticancer effect, but with no description about any effect of preventing or treating asthma and chronic obstructive pulmonary disease, arthritis, atopic dermatitis and degenerative brain diseases. Particularly, there is no substantial studies on 7-(3′,4′-dialkoxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidine compounds of the present invention.
